[3+2] cycloaddition reactions of proline benzyl ester nitrone with alkenes and alkynes

Article abstract of DOI:10.1055/s-1999-2682

Proline-based nitrone 2a has been synthesized. It readily underwent [3+2] cycloadditions with a variety of alkene and alkyne substrates to give isoxazolidines and isoxazolines, respectively, with good to excellent regio- and diastereoselectivity.

Full text of DOI:10.1055/s-1999-2682

LETTER
653
[3+2] Cycloaddition Reactions of Proline Benzyl Ester Nitrone with Alkenes
and Alkynes
Ronald C. Bernotas,* Jeffrey S. Sabol, Lily Sing, Dirk Friedrich
Hoechst Marion Roussel, Inc., Box 6800, Rt.202-206, Bridgewater, NJ 08807 USA
Fax (1)-908-231-3577; E-mail: ronald.bernotas@hmrag.com
Received 7 March 1999
The benzyl ester of proline was chosen as the starting ma-
Abstract: Proline-based nitrone 2a has been synthesized. It readily
terial since it was commercially available and the benzyl
underwent [3+2] cycloadditions with a variety of alkene and alkyne
group provided a convenient handle during synthetic ma-
substrates to give isoxazolidines and isoxazolines, respectively,
nipulations. Direct oxidation of proline benzyl ester 1a
was accomplished using a Na2WO4-catalyzed hydrogen
peroxide oxidation7 to give nitrone 2a in 30-40% yield as
a low melting solid. When a sample of 2a was heated un-
der nitrogen in d8-toluene for 2 days at 110 °C, no decom-
position was detected by 1H or 13C NMR.
with good to excellent regio- and diastereoselectivity.
Key words: [3+2] cycloaddition, isoxazolidine, isoxazolin, nitrone
As part of an effort to build combinatorial libraries of var-
ious chemical classes, we have investigated potential scaf-
folds which would lead to molecules with at least two sites
for chemical modification. Nitrones represent attractive
scaffolds since they undergo [3+2] cycloaddition reac-
tions with a diverse range of alkenes and alkynes to afford
versatile isoxazolidine and isoxazoline-type products.1
These cycloadducts are useful intermediates for the cre-
ation of chemical libraries because they are readily modi-
fied by reduction,2 oxidative alkylation,3 and even
oxidation to other nitrones.4 Therefore the cycloadducts
represent a key branch point toward chemical diversity.
One appealing scaffold candidate is cyclic nitrone 2a,
closely related to known 2b (Scheme 1).5 The latter nitro-
ne has been synthesized several times but, to our know-
ledge, it has not been utilized in cycloaddition reactions.
Reaction of 2a with various substrates and subsequent re-
ductive cleavage of cycloadducts 3 would produce α-sub-
stituted proline derivatives. While cycloadditions of this
achiral nitrone to achiral substrates would afford racemic
mixtures, our initial efforts focused on this simpler system
with the expectation of a future chiral version. We report
here the synthesis of 2a and its cycloaddition reactions
with a range of substrates, supporting the use of nitrones
as building blocks for combinatorial libraries.6
With 2a in hand, we examined its cycloaddition reactions
with alkenes and alkynes (Table 1). Substrates for cy-
cloaddition included simple alkenes such as 1-hexene and
4-allylanisole, aryl substituted alkenes such as styrene,
and Michael acceptors such as ethyl crotonate. Alkyne
substrates included phenyl acetylene and methyl propi-
olate. In a typical procedure, the nitrone and 2-4 equiva-
lents of substrate were heated in toluene under nitrogen at
80-110 °C. Concentration of the reaction mixture fol-
lowed by flash chromatography afforded the purified
products.
Not surprisingly, reaction times varied considerably de-
pending on the substrate. In general, Michael-type sys-
tems such as methyl propiolate and ethyl crotonate reacted
fastest, with the cycloaddition essentially complete after
just 1-3 hours. Alkynes also reacted rather quickly, possi-
bly helped by both the minimal steric demands of the lin-
ear alkyne group and its increased reactivity.
Monosubstituted alkenes were considerably slower to un-
dergo cycloaddition, typically requiring 1 to 2 days at re-
flux in toluene to near completion. The most hindered
alkene, tetrahydropyran, gave only a 14% yield of the cy-
cloadduct even after 2 days at reflux. The product, of un-
determined stereochemistry, appeared to slowly revert to
1
starting materials in CDCl3 as determined by H NMR
analysis. Traces of acid in the solvent may have contribut-
ed to the cycloreversion.
The regioselectivity and diastereoselectivity of the cyclo-
additions was determined using NMR, including exten-
sive NOE and NOESY analysis of cycloadducts 3.8 The
cycloadditions exhibited very high regioselectivity af-
fording the products anticipated.8,9 Specifically, the nitro-
ne oxygen added to the end of the multiple bond at which
the substitutent either stabilizes formation of partial posi-
tive charge (e.g. alkyl, aromatic and alkoxy) or is less de-
stabilizing (e.g. away from the ester). Steric factors may
also contribute to the regioselectivity.
Scheme 1
Synlett 1999, No. 5, 653–655 ISSN 0936-5214 © Thieme Stuttgart · New York

654
R. C. Bernotas et al.
LETTER
The cycloadditions of nitrone 2a were essentially diaste- In conclusion, we have synthesized nitrone 2a and inves-
reospecific. Ample precedent exists for diastereoselectiv- tigated its [3+2] cycloaddition reactions with alkenes and
ity in cycloadditions of other cyclic nitrones.10 These alkynes. The nitrone reacted with a variety of substrates to
reactions generally favor exo-mode addition consistent give a diverse set of cycloadducts. The cycloadditions
with our observed diastereomer preference (Scheme 2). proceeded with excellent regioselectivity and diastereose-
However, certain cycloadditions are reversible and there- lectivity. Since the cycloadducts are immediate precursors
fore the product distribution may reflect thermodynamic to α-substituted proline derivatives, the methodology
rather than kinetic control.9,11
should allow the synthesis of proline derivatives not readi-
ly accessible by other methods.12 Experiments are under-
way to develop a chiral version of the nitrone to address
the limitation of obtaining achiral products. The results of
this investigation will be reported in due course.
Figure
Scheme 2
Synlett 1999, No. 5, 653–655 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
[3+2] Cycloaddition Reactions of Proline Benzyl Ester Nitrone with Alkenes and Alkynes
655
(7) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J. Org. Chem. 1990, 55, 1736-1744.
(8) For a discussion of the stereochemistry of alkene-cyclic
nitrone reactions see: Tufariello, J. T. Accts. Chem. Res. 1979,
12, 396-403.
(9) For reviews, see Bianchi, G.; De Micheli, C.; Gandolfi, R.
Angew. Chem., Int. Ed. Engl. 1979, 18, 721-738 and Bianchi,
G.; Gandolfi, R. “1,3-Dipolar Cycloreversions” in 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley
Interscience: New York, 1984; Vol. 2, p. 451.
(10) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Masanori, S. Chem. Commun. 1996, 1861-
1862.
References and Notes
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1-158 and reference 11.
(2) LeBel, N. A.; Balasubramanian, N. J. Am. Chem. Soc. 1989,
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(3) Murahashi, S.-I.; Kodera, Y.; Hosomi, T. Tetrahedron Lett.
1988, 29, 5969-5952.
(4) See LeBal, N. A.; Spurlock, L. A. J. Org. Chem. 1964, 29,
1337-1339, Holmes, A. B.; Hughes, A. B.; Smith, A. L.
Synlett. 1991, 47-48 and de March, P.; Figueredo, M.; Font, J.;
Milan, S.; Alvarez-Larena, A.; Piniella, J. F.; Molins, E.
Tetrahedron 1997, 53, 2979-2988.
(5) Marcantoni, E.; Petrini, M.; Polimanti, O. Tetrahedron Lett.
1995, 36, 3561-3562, Murahashi, S.; Mitsui, H.; Shiota, T.;
Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1734-1744,
Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025-6028,
Murray, R. W.; Iyanar, K. J. Org. Chem. 1996, 61, 8099-8102.
A 3,4-disubstituted analog of 2b has recently been reported,
but was not used in cycloaddition reactions: see Maeda, H.;
Kraus, G. A. J. Org. Chem. 1997, 62, 2314-2315.
(11) For leading references see: Torssell, K. B. G. Nitrile Oxides,
Nitrones, and Nitronates in OrganicSynthesis; VCH:
New York, 1988; p 22.
(12) See Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704-
2708.
Article Identifier:
1437-2096,E;1999,0,05,0653,0655,ftx,en;S08298ST.pdf
(6) 1,3-Dipolar cycloadditions have been used to make
combinatorial libraries on solid support. See Hollinshead, S.
P. Tetrahedron Lett. 1996, 37, 9157-9160.
Synlett 1999, No. 5, 653–655 ISSN 0936-5214 © Thieme Stuttgart · New York